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The antibody cocktails from Eli Lilly and Regeneron Pharmaceuticals have now received emergency use authorization from the Food and Drug Administration (FDA) in the United States for the treatment of Covid-19. These antibodies attach themselves to the spike protein of the virus and prevent it from entering cells. However, with the peak mutating into new variants, there is concern that some of these treatments will become ineffective.
The Eli Lilly treatment consists of two antibodies that are infused into patients intravenously. The European Medicines Agency (EMA) is reviewing this cocktail. One of these antibodies, bamlanivimab, was cleared by the FDA on its own in November. In January, Eli Lilly reported that it reduced the risk of developing symptomatic Covid-19 by up to 80% when given to residents of nursing homes in the United States.
The FDA has cleared the Lilly combo for mild to moderate Covid-19 patients who are at risk for serious illness. It had also cleared two Regeneron antibodies for mild to moderate Covid-19 in November (casirivimab and imdevimab). Former US President Donald Trump claims the Regeneron combo cured him when he contracted Covid-19 late last year.
Monoclonal antibodies are synthetic proteins made in culture of mammalian cells. They mimic our natural antibodies. A number of these are successful anti-inflammatories, and two that block the pro-inflammatory cytokine interleukin-6 reduce mortality in critically ill Covid-19 patients.
In 2019, seven of the top 10 best-selling drugs were monoclonal antibodies. Some of the newer monoclonal viruses target viruses. Indeed, the FDA approved a cocktail of three monoclonal antibodies of Regeneron against the Ebola virus in 2020. The latter catch a viral glycoprotein which binds to the cell receptor. The FDA has approved another antibody (Ebanga) that interferes with binding.
Free Covid
For Sars-CoV-2, most monoclonal antibodies are designed to target the part of the spike protein that binds to the human Ace2 receptor. “You can basically make unlimited amounts of this antibody in a bioreactor as a biological drug,” says James Crowe, an immunologist at Vanderbilt University Medical Center in the United States.
This approach differs from the use of convalescent plasma, which is collected from recovered Covid-19 patients. Convalescent plasma can be injected into sick patients, but contains thousands of antibodies against many different antigens. “Only a small percentage of these antibodies would be for the coronavirus,” Crowe says. “Whereas with monoclonal antibodies, 100% are for the coronavirus, so it’s more like a drug.” Convalescent plasma is a much more variable product, as it comes from individual patients.
To develop new monoclonal antibodies against Sars-CoV-2, scientists first select from thousands of potential candidates, then mix a few with viruses in the lab to identify the most potent ones. It’s like looking for a needle in a haystack [initially]Crowe says. “The next step is usually to test them on small animals to see if they are protective, and then on larger animals, like macaque monkeys.
It all takes time, which is why Crowe was so impressed with Eli Lilly’s progress. “ They were at the clinic in June 2020 which is a miracle. The fastest ever, ”says Crowe. It was bamlanivimab, discovered in a blood sample taken from one of the first patients in the United States to recover from Covid-19.
Unfortunately, the antibodies have mostly disappointed in the treatment of critically ill Covid-19 patients. “The results of very ill patients have been somewhat lackluster,” says Aashish Manglik, a biochemist at the University of California at San Francisco in the United States. “They have to administer huge doses of the vaccine, almost eight grams per patient. Crowe explains that “the longer you wait, the harder it is to treat” with antibodies.
Another problem is that existing antibody therapies require intravenous infusion. This means that mild or moderately ill patients should go to a medical facility, when they are probably the most contagious. “The logistics required to bring many people to such a facility make it very difficult to deploy the antibody approach on a large scale,” says Manglik. Crowe describes intravenous infusion as a “moderate barrier to frequent use”.
The ability of the virus to escape an antibody is reasonably high
James Crowe, Vanderbilt University Medical Center
AstraZeneca has five ongoing Phase 3 clinical trials with a two-antibody combo (designated AZD7442), developed in Crowe’s lab at Vanderbilt. This cocktail can be administered as an injection, and a trial with 5,000 participants will test it as a preventive measure. “It’s an intramuscular injection, so it will be much easier to use than intravenous infusions,” Crowe explains.
Cocktails are considered more favorably than isolated antibodies. An antibody developed by Vir Biotechnology and GSK is combined with an Eli Lilly antibody (bamlanivimab) to treat patients in a new trial. Both bind to different parts of the spike protein.
“The ability of the virus to escape an antibody is reasonably high,” says Crowe. “But its ability to escape two antibodies, against different parts of the virus, is very low.” Coveralls are insurance against the escape of the virus.
Spike swizzle
This problem is all the more critical since certain variants have mutated advanced proteins and escape certain antibodies. One of Eli Lilly’s antibodies likely won’t work against some of the newer variants, Crowe says, while Regeneron’s antibodies have a moderate effect on mutants.1 “As the new variants spread around the world,” Crowe says, some of these monoclonal antibodies may not be optimal against certain strains of the virus.
The best solution to saving patients infected with coronavirus is to combine approved antibodies from different companies, explains immunologist Hans-Martin Jäck of the University of Erlangen-Nuremberg in Germany, who developed two monoclonal antibodies against the peak SARS-CoV-2. A testing site could collect approved antibodies and test them against a new mutant in a few weeks, he says. “If you combine the most effective in one cocktail, then one of them will definitely work against any new variant. However, this concept would require some thought on the part of drug regulatory authorities.
Researchers are also looking at alternative approaches. Manglik has developed fully synthetic nanobodies against the spike protein, from a library of two billion compounds. “We are doing animal testing and hope to start clinical trials in the coming months. The nanobody could be administered directly to the nose or respiratory tract, he adds.
Nanobodies are small proteins originally identified in camelid species like llama and alpaca, which make these mini-versions of antibodies. The first such miniature antibody was approved for clinical use by the European Medicines Agency in 2018: a Sanofi nanobody (Cablivi) for a rare blood coagulation disorder.
Another strategy is to develop “broadly neutralizing antibodies” to target a range of related viruses. Laura Walker, of the American biotechnology company Adagio Therapeutics, and her colleagues have designed an antibody that neutralizes Sars-CoV-2,2 but also related coronaviruses, including Sars-CoV. It does this by targeting a conserved region of the receptor binding domain, which they call “an Achilles heel” and a possible target of future pan-Sars vaccines. An extended half-life version of the antibody (ADG20) entered the clinical trial a few weeks ago and will be given by injection.
Monoclonal antibodies can be used as a prophylaxis immediately after a person is exposed to Sars-CoV-2, unlike a vaccine. For now however, existing monoclonal antibodies have to be infused and therefore remain a difficult logistical option in many settings.
Unlike anti-inflammatory conditions, Jäck says that “ the antibodies will not be a blockbuster for the coronavirus, because those who will need them are only those who cannot get vaccinated, ” such as people who are immunocompromised. However, he adds that antibody therapies will certainly save lives.
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